Description:

The current trial was a phase II dose-ranging trial to study the safety and efficacy of celivarone as compared with amiodarone and placebo in patients with cardiomyopathy and recent implantable cardioverter defibrillator (ICD) therapy. Celivarone is a new AAD with Vaughn Williams Class I-IV effects.

Hypothesis:

Celivarone would be superior to amiodarone and placebo in preventing ventricular tachycardia/ventricular fibrillation (VT/VF) triggered ICD interventions or sudden death.

Concomitant Medications:

Principal Findings:

A total of 486 patients were enrolled at 151 centers in 26 countries, 109 to placebo, 53 to amiodarone, and 324 to celivarone. Baseline characteristics were similar between the different arms. About 24% of the patients were age ≥75 years, 92% were White, and 64% had a body mass index <30. The mean left ventricular ejection fraction (LVEF) was 29.1%, with an EF < 35% in 65% of the patients. About 85% of the patients had a creatinine clearance of ≥50, 71% had coronary artery disease, 51% had dilated ischemic cardiomyopathy, and 6% had prior stroke.

The primary endpoint of VT/VF triggering ICD intervention or sudden cardiac death (SCD) was similar between the placebo, amiodarone, and celivarone 50 mg, 100 mg, and 300 mg arms (61.5% vs. 45.3% vs. 67.0% vs. 58.8% vs. 54.9%, p > 0.05 for all vs. placebo). The vast majority of events were VT/VF. The secondary endpoint of first shock or death was also similar between the different arms, as were ICD shocks (p > 0.05) and all-cause mortality (5.5% vs. 17.0% vs. 7.3% vs. 5.9% vs. 9.7%, p > 0.05 vs. placebo). The incidence of treatment-related adverse events resulting in permanent discontinuation of study drug was lowest with placebo (16.5%), intermediate with celivarone (about 24%), and highest with amiodarone (31.4%).

Interpretation:

The results of this trial indicate that celivarone, a novel AAD with a profile similar to amiodarone and dronedarone, is not effective in reducing VT/VF shocks or SCD as compared with amiodarone or placebo in the doses studied. However, the burden of this problem in the population studied in this trial (low EF with history of VT/VF) was high (about 50-60% of all patients). Further, ICD shocks are associated with increased morbidity (e.g., post-traumatic stress disorder, depression). This highlights the importance of conducting further studies to identify agents or strategies that may help ameliorate this problem.

References:

Kowey PR, Crijns HJ, Aliot EM, et al., on behalf of the ALPHEE Study Investigators. Efficacy and Safety of Celivarone, With Amiodarone as Calibrator, in Patients With an Implantable Cardioverter-Defibrillator for Prevention of Implantable Cardioverter-Defibrillator Interventions or Death: The ALPHEE Study. Circulation 2011;Nov 14:[Epub ahead of print].